The incidence of kidney stones in women is lower than in men throughout adult life. However, stone incidence has been reported to increase in women during the 6th decade of life, while for men it begins to decrease. A retrospective analysis of patient data obtained during previous funding cycles of this P01 has disclosed a significant increase in urinary calcium excretion during the 6th decade in women stone-formers. This time corresponds to the onset of menopause in many women. Moreover, udnary calcium excretion was substantially lower in postmenopausal women treated with estrogen than in those who were not, commensurate with a similar decline in urinary saturation of calcium oxalate. These findings are consistent with the possibility that estrogen deficiency increases the risk of stone formation. Our central hypothesis to be tested in this proposal is that the apparent increase in stone formation rate following menopause is in part due to pdmary impairment of renal tubular calcium reabsorption from estrogen lack. This hypothesis will be tested through four specific aims representing a translational approach to uncover the mechanism(s) of renal calcium leak. The specific aims are: (1) evaluate the effects of short-term estrogen treatment on the renal handling of calcium and the propensity for stone formation in normal postmenopausal women as well as postmenopausal women with kidney stones: (2) quantitate the effect of estrogen replacement on calcium transport via clearance studies as well as in vivo microperfusion of the proximal tubule, loop of Henle and distal convoluted tubule in the ovariectomized (OVX) rat; (3) characterize estrogen-dependent regulation of calbindin-D28K gene expression in renal tubular cells; and (4) examine the mechanism for calbindin-D28K regulation of calcium entry via epithelial calcium channel (ECaC). These proposed studies represent a translational approach that will characterize the effect of estrogen on renal calcium handling using clinical, whole animal, and molecular models. It is anticipated that the findings will expand our understanding of hormonal regulation of renal calcium transport, offer a mechanism for increased stone propensity in postmenopausal women, and open new avenues for investigation of potential countermeasures to stone formation not only for this select group of patients but for the stone-forming population in general.